Systems Epigenomics of Persistent Bloodstream Infection
持续性血流感染的系统表观基因组学
基本信息
- 批准号:10551703
- 负责人:
- 金额:$ 230.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-10 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAlgorithmsAnti-Infective AgentsAntibiotic ResistanceAntibiotic TherapyAntibioticsAntifungal AgentsAntigensAutomobile DrivingBacteremiaBioinformaticsBloodBlood CirculationCandidaCandida albicansCenters for Disease Control and Prevention (U.S.)Chromosomal RearrangementClinicalCommunicable DiseasesComputer ModelsComputing MethodologiesDNA MethylationDataData SetDetectionDiagnosticDiseaseDisseminated candidiasisEmergency SituationEpigenetic ProcessEtiologyExperimental ModelsFungemiaGene ExpressionGene RearrangementGeneticGenotypeGoalsHealthcareHematogenousHospital MortalityHumanImmuneImmune EvasionImmune responseImmune systemImmunityImmunologic MemoryImmunotherapeutic agentIn VitroInfectionIntensive Care UnitsInterventionLaboratoriesLaboratory StudyLength of StayLibrariesLifeMacrophageMediatingMemoryMethodsMicrobial BiofilmsModelingMolecularMorbidity - disease rateNosocomial InfectionsOrganOutcomePathogenesisPatientsPatternPattern recognition receptorPhenotypePredispositionProcessProductivityReceptor SignalingRefractoryResearchResearch Project GrantsResistanceRiskSTAT proteinSTAT1 proteinSepsisSpecificityStaphylococcus aureusStressStudy modelsSystemSystems BiologyTechnologyTestingTherapeuticTissuesTrainingTranslatingUnited States National Institutes of HealthVariantVirulenceWorkantimicrobialantimicrobial drugantimicrobial tolerancebiobankcandidemiacell injurychronic infectioncomplex datacytokinedata managementeffective therapyepigenetic memoryepigenomeepigenomicshigh riskimprovedin vivoinnate immune mechanismsinnovationinsightmethicillin resistant Staphylococcus aureusmethylomicsmortalitymouse modelneutrophilnovelnovel strategiespathogenpharmacologicprediction algorithmpredictive modelingpreventprogramsprospectiveprototyperesponsescreeningsexsuccesssynergismtherapeutic candidatevaccine strategy
项目摘要
PROJECT ABSTRACT
Persistent bloodstream infections are life-threatening infectious disease emergencies posing significant challenges
to effective treatment. Such infections occur when a pathogen is susceptible to an anti-infective agent in vitro but is not
cleared from the bloodstream in vivo when that anti-infective agent is used appropriately. As a result, anti-infective usage
increases, accelerating alarming increases in anti-infective resistance. This vicious cycle of persistence driving anti-
infective escalation driving resistance is an NIH high–priority concern. Bloodstream infections caused by
Staphylococcus aureus (SA) or Candida albicans (CA) are increasingly common. Of urgent concern, up to 35% of
patients with methicillin-resistant SA (MRSA) persistent bacteremia succumb even on gold-standard therapy. Likewise,
in patients with hematogenously disseminated candidiasis (HDC), mortality is 39% overall and 47% in those in the
intensive care unit, despite appropriate treatment. A disease mystery is central to such infections: the causative
pathogen is susceptible to antimicrobials in laboratory testing—but not in the human being. Importantly, persistence
reflects a unique type of treatment-refractory infections distinct from classical antibiotic resistance. Rather, persistent
MRSA or CA are elusive: they adapt to host immune responses and antibiotic stresses uniquely in vivo and then revert
quickly in vitro. Presently, there are few therapeutic options for persistent MRSA or CA bloodstream infections. Hence,
there is a critical, unmet need to understand the unique interactions of the human, pathogen and therapeutic factors
driving persistence outcomes.
Based on our extensive preliminary data, we believe that persistent infections caused by MRSA and CA result from
a three-way interaction of the pathogen, host immune response and antimicrobial agent in vivo. We hypothesize that
persistent isolates: 1) have specific epigenomes to enable persistence; 2) subvert innate immune programming
and memory for immune evasion; 3) evoke non-protective or maladaptive immune responses; and 4) exploit
contextual immunity as persistence reservoirs. We further posit that conventional approaches to study this clinically
urgent phenomenon are insufficient to understand it. We have developed three independent but synergistic research
Projects to overcome these limitations. Each Project brings proven strengths and innovative approaches to bear on
Specific Aims that synergize via a systems-based approach supported by outstanding technology, bioinformatics and
computational Cores. Here, we will use state-of-the-art technologies to comprehensively analyze the genetics and
epigenetics of pathogens and the host immune system in context of antimicrobial therapy in laboratory studies and
experimental models of infection. In turn, these data will be analyzed using powerful bioinformatics and computational
methods to detect hidden patterns within large complex datasets. By understanding these factors and their interactions,
new approaches to identify and treat high risk patients can be developed and applied to improve and save lives. These
goals are ideally aligned with priorities of the National Institutes of Health and Centers for Disease Control & Prevention.
项目摘要
项目成果
期刊论文数量(0)
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Michael R Yeaman其他文献
Michael R Yeaman的其他文献
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{{ truncateString('Michael R Yeaman', 18)}}的其他基金
Epigenomic Mechanisms & Contextual Immunity in Persistent MRSA Bacteremia
表观基因组机制
- 批准号:
10551708 - 财政年份:2023
- 资助金额:
$ 230.46万 - 项目类别:
Systems Immunolobiology of Antibiotic-Persistent MRSA Infection
抗生素持续性 MRSA 感染的系统免疫学
- 批准号:
9246423 - 财政年份:2016
- 资助金额:
$ 230.46万 - 项目类别:
Systems Immunolobiology of Antibiotic-Persistent MRSA Infection
抗生素持续性 MRSA 感染的系统免疫学
- 批准号:
9108773 - 财政年份:2016
- 资助金额:
$ 230.46万 - 项目类别:
Novel Context-Activated Protide Anti-Infectives
新型环境激活蛋白肽抗感染药
- 批准号:
7218790 - 财政年份:2007
- 资助金额:
$ 230.46万 - 项目类别:
Novel Context-Activated Protide Anti-Infectives
新型环境激活蛋白肽抗感染药
- 批准号:
7429814 - 财政年份:2007
- 资助金额:
$ 230.46万 - 项目类别:
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